Chemical Activators of VCP, an Unfoldase Required for Proteostasis
Event Details
- Type
- Monday Lecture Series
- Speaker(s)
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Tarun Kapoor, Ph.D., Pels Family Professor and head, Selma and Lawrence Ruben Laboratory of Chemistry and Cell Biology, The Rockefeller University
- Speaker bio(s)
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Dr. Kapoor will discuss his lab's recent efforts to identify and characterize chemical activators of ATPase mechanoenzymes. The loss of function of AAA (ATPases associated with diverse cellular activities) mechanoenzymes has been linked to diseases, and chemical probes that activate these proteins can be powerful tools to probe function and test therapeutic hypotheses. Unlike an inhibitor that can bind a single conformational state of an enzyme to block activity, activator binding must be permissive to different conformational states needed for function. However, we do not know how any of the ~100 AAA proteins expressed in humans can be activated by drug-like small molecules. The Kapoor Lab has focused on VCP, an AAA unfoldase with essential roles in protein turnover and quality control. Loss-of-function mutations in VCP have been linked to degenerative diseases in multiple organs and tissues. The lab has identified and optimized compounds that stimulate VCP’s activity and have determined cryo-EM structures (~2.9-3.5 Å resolution) of activator-VCP complexes in apo and ADP-bound states. In ongoing work, structure-guided design has led to more potent VCP activators that may stimulate autophagy, a lysosomal degradation pathway critical for disposing harmful cellular materials. Together, their findings uncover a druggable allosteric site that can also be occupied by VCP’s C-terminal tail to control activity, suggesting a mechanism of small molecule mimicry of mechanoenzyme regulation.
Tarun Kapoor earned his bachelor's degrees in chemistry and biology from the California Institute of Technology in 1993. He received his Ph.D. in chemistry from Harvard University in 1998. After his postdoc at Harvard Medical School, he joined Rockefeller in 2001 as an assistant professor, becoming an associate professor in 2005 and the Pels Family Professor in 2008.Kapoor has received an Irving Sigal Young Investigator Award and an Irma T. Hirschl/Monique Weill-Caulier Trust Scholar Award. He has also been named a Leukemia and Lymphoma Society Scholar and a Pew Biomedical Scholar, among various awards and honors.
MLS lectures are only open to the RU community. This lecture will be taking place in Carson Family Auditorium only. It will not be available virtually/on Zoom. - Open to
- Campus Only